| RRC ID |
88087
|
| Author |
Shalash R, Solomon DM, Levi-Ferber M, von Chrzanowski H, Atrash MK, Nakar B, Avivi MY, Hauschner H, Swisa A, Meléndez A, Shav-Tal Y, Henis-Korenblit S.
|
| Title |
HLH-30/TFEB Rewires the Chaperone Network to Promote Proteostasis Upon Perturbations to the Coenzyme A and Iron-Sulfur Cluster Biosynthesis Pathways.
|
| Journal |
Aging Cell
|
| Abstract |
The maintenance of a properly folded proteome is critical for cellular function and organismal health, and its age-dependent collapse is associated with a wide range of diseases. Here, we find that despite the central role of Coenzyme A as a molecular cofactor in hundreds of cellular reactions, inhibition of the first and rate-limiting step in CoA biosynthesis can be beneficial and promote proteostasis. Impairment of the cytosolic iron-sulfur cluster formation pathway, which depends on Coenzyme A, similarly promotes proteostasis and acts in the same pathway. Proteostasis improvement by interference with the Coenzyme A/iron-sulfur cluster biosynthesis pathways is dependent on the conserved HLH-30/TFEB transcription factor. Strikingly, under these conditions, HLH-30 promotes proteostasis by potentiating the expression of select chaperone genes, providing a chaperone-mediated proteostasis shield, rather than by its established role as an autophagy and lysosome biogenesis-promoting factor. This reflects the versatile nature of this conserved transcription factor, which can transcriptionally activate a wide range of protein quality control mechanisms, including chaperones and stress response genes alongside autophagy and lysosome biogenesis genes. These results highlight TFEB as a key proteostasis-promoting transcription factor and underscore it and its upstream regulators as potential therapeutic targets in proteostasis-related diseases.
|
| Volume |
24(6)
|
| Pages |
e70038
|
| Published |
2025-6-1
|
| DOI |
10.1111/acel.70038
|
| PMID |
40304211
|
| PMC |
PMC12151917
|
| MeSH |
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / metabolism
Coenzyme A* / biosynthesis
Coenzyme A* / metabolism
Humans
Iron-Sulfur Proteins* / biosynthesis
Iron-Sulfur Proteins* / metabolism
Molecular Chaperones* / metabolism
Proteostasis*
|
| Resource |
| C.elegans |
tm8231
tm9231
tm1978 |
